Human traumatic brain injury (TBI) is heterogeneous and may encompass aspects of both focal and diffuse pathology. The mechanisms of cell death and injury associated with focal and diffuse TBI may involve unique, multiple degenerative signaling pathways. Therefore, therapeutic strategies must be developed that are targeted toward the relative contribution of these specific pathogenic cascades. Moreover, since the cellular and molecular sequelae of TBI are so diverse, it is likely that some form of polypharmaceutical (cocktail or sequential) therapy will be maximally effected. Lateral fluid-percussion (FP) brain injury in the rat will be used in all studies, since it models aspects of both focal and diffuse brain injury. In Specific Aim 1, we will evaluate whether the sequelae of diffuse brain (white matter) injury and pathways leading to necrotic cell death associated with focal brain (gray matter) injury may be reversible using pharmacotherapy directed toward calcium entry into cells or by limiting calcium-induced proteolysis of the cytoarchitecture. Specific Aim 2 will evaluate whether the cell death and behavioral disability following lateral FP injury, which appears to be associated, in part, with caspase-mediated apoptosis, may be attenuated by strategies which inhibit the caspase family of proteases. Specific Aim 3 will evaluate whether a timed sequential combination of pharmacotherapies directed at reversing both calcium-induced cytoskeletal breakdown and apoptotic cell death will be more efficacious than either compound alone in the lateral FP model of mixed focal and diffuse brain injury. Finally, Specific Aim 4 will use aRNA amplification and DNA microarrays in mRNA from cells in injured areas (1) to relate the genomic response to trauma to the biomechanical strain field "maps" developed in Core B and (2) to identify the molecular characteristics or "fingerprint" of cells that have been protected by our chosen drug treatments. It is our hope that these studies will lead to the development of novel therapeutic strategies for the treatment of clinical brain injury.